Developmental pharmacogenetics in pediatric rheumatology: utilizing a new paradigm to effectively treat patients with juvenile idiopathic arthritis with methotrexate.

Becker ML, Leeder JS - Hum Genomics Proteomics (2010)

Bottom Line:
In addition to differences in drug administration, factors that affect pharmacokinetics and pharmacodynamics such as genetic variation may explain individual differences in drug biotransformation.However, the pediatric population has an additional factor to consider, namely the ontogeny of gene expression which may result in variation throughout growth and development.We review the current understanding of methotrexate biotransformation and the concept of ontogeny, with further discussion of how to implement a developmental pharmacogenomics approach in future studies.

ABSTRACTAlthough methotrexate is widely used in clinical practice there remains significant lack of understanding of its mechanisms of action and the factors that contribute to the variability in toxicity and response seen clinically. In addition to differences in drug administration, factors that affect pharmacokinetics and pharmacodynamics such as genetic variation may explain individual differences in drug biotransformation. However, the pediatric population has an additional factor to consider, namely the ontogeny of gene expression which may result in variation throughout growth and development. We review the current understanding of methotrexate biotransformation and the concept of ontogeny, with further discussion of how to implement a developmental pharmacogenomics approach in future studies.

fig1: Comparison of MTXglun subgroups between oral (PO) and subcutaneous (SC) routes of administration. (a) Short chain polyglutamates (MTXglu1+2) were more predominant with PO administration, and (b) higher concentrations of long chain polyglutamates (MTXglu3-5) were more predominant with SC administration. Box and whisker plots are superimposed on data from individual patients. Boxes include the median and interquartile range, and whiskers indicate the 10th and 90th percentiles.

Mentions:
In order to better identify factors that may contribute to the inconsistencies in response and toxicity to MTX, we sought to characterize the extent of variability of intracellular MTXglun concentrations in our JIA patient population, and to investigate variables that may contribute to MTXglun variability. We have measured intracellular MTXglun concentrations in a cohort of 104 JIA patients. In this cohort, total intracellular MTXglun (MTXgluTOT, the sum of all individual MTXglun) concentrations varied 40-fold with a mean of 85.4 ± 48.8 nmol/L. Concentrations of MTXglu1-7 were measured individually and as a percentage of each patient's MTXgluTOT. MTXglu3 was the most prominent subtype identified, comprising 42% of MTXgluTOT, and was most highly correlated with MTXgluTOT (r = 0.96) [41]. Route was a significant predictor of MTXglu1-5 subtype. Higher concentrations of MTXglu1+2 were observed in patients receiving oral doses of MTX, whereas higher concentrations of MTXglu3-5 were observed in patients receiving subcutaneous doses of MTX (P <.0001), even after correcting for dose. (Figure 1) [41]. These findings were also supported further by hierarchical clustering, which revealed distinct clusters of patients with higher proportions of MTXglu1+2 and a second cluster of patients in whom MTXglu3–5 predominated (Figure 2). After controlling for MTX dose, subjects with higher proportions of MTXglu1+2 were more likely to be receiving oral MTX (P < .0001). Those with higher proportions of MTXglu3-5 were more likely to be receiving subcutaneous MTX (P = .0097) [42]. In agreement with Dolezalova and colleagues, we did not find a strong association of MTXglun concentrations (total or long chain) with MTX response (unpublished data), but we are actively investigating associations with clinical outcomes such as GI toxicity and hepatic enzyme elevation. Our experience demonstrates that MTXglun concentrations can be reliably measured in children and are extensively variable [41], yet the contributors to this variability are not fully explored.

fig1: Comparison of MTXglun subgroups between oral (PO) and subcutaneous (SC) routes of administration. (a) Short chain polyglutamates (MTXglu1+2) were more predominant with PO administration, and (b) higher concentrations of long chain polyglutamates (MTXglu3-5) were more predominant with SC administration. Box and whisker plots are superimposed on data from individual patients. Boxes include the median and interquartile range, and whiskers indicate the 10th and 90th percentiles.

Mentions:
In order to better identify factors that may contribute to the inconsistencies in response and toxicity to MTX, we sought to characterize the extent of variability of intracellular MTXglun concentrations in our JIA patient population, and to investigate variables that may contribute to MTXglun variability. We have measured intracellular MTXglun concentrations in a cohort of 104 JIA patients. In this cohort, total intracellular MTXglun (MTXgluTOT, the sum of all individual MTXglun) concentrations varied 40-fold with a mean of 85.4 ± 48.8 nmol/L. Concentrations of MTXglu1-7 were measured individually and as a percentage of each patient's MTXgluTOT. MTXglu3 was the most prominent subtype identified, comprising 42% of MTXgluTOT, and was most highly correlated with MTXgluTOT (r = 0.96) [41]. Route was a significant predictor of MTXglu1-5 subtype. Higher concentrations of MTXglu1+2 were observed in patients receiving oral doses of MTX, whereas higher concentrations of MTXglu3-5 were observed in patients receiving subcutaneous doses of MTX (P <.0001), even after correcting for dose. (Figure 1) [41]. These findings were also supported further by hierarchical clustering, which revealed distinct clusters of patients with higher proportions of MTXglu1+2 and a second cluster of patients in whom MTXglu3–5 predominated (Figure 2). After controlling for MTX dose, subjects with higher proportions of MTXglu1+2 were more likely to be receiving oral MTX (P < .0001). Those with higher proportions of MTXglu3-5 were more likely to be receiving subcutaneous MTX (P = .0097) [42]. In agreement with Dolezalova and colleagues, we did not find a strong association of MTXglun concentrations (total or long chain) with MTX response (unpublished data), but we are actively investigating associations with clinical outcomes such as GI toxicity and hepatic enzyme elevation. Our experience demonstrates that MTXglun concentrations can be reliably measured in children and are extensively variable [41], yet the contributors to this variability are not fully explored.

Bottom Line:
In addition to differences in drug administration, factors that affect pharmacokinetics and pharmacodynamics such as genetic variation may explain individual differences in drug biotransformation.However, the pediatric population has an additional factor to consider, namely the ontogeny of gene expression which may result in variation throughout growth and development.We review the current understanding of methotrexate biotransformation and the concept of ontogeny, with further discussion of how to implement a developmental pharmacogenomics approach in future studies.

ABSTRACTAlthough methotrexate is widely used in clinical practice there remains significant lack of understanding of its mechanisms of action and the factors that contribute to the variability in toxicity and response seen clinically. In addition to differences in drug administration, factors that affect pharmacokinetics and pharmacodynamics such as genetic variation may explain individual differences in drug biotransformation. However, the pediatric population has an additional factor to consider, namely the ontogeny of gene expression which may result in variation throughout growth and development. We review the current understanding of methotrexate biotransformation and the concept of ontogeny, with further discussion of how to implement a developmental pharmacogenomics approach in future studies.